This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The current project utilized positron emission tomography (PET) neuroimaging and functional magnetic resonance imaging (fMRI) techniques in nonhuman primates as a noninvasive approach to investigate cocaine-induced functional changes in central nervous system activity. A recently published study was the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates. Following non-contingent administration of cocaine, brain activation maps normalized to global flow showed prominent cocaine-induced activation of prefrontal cortex localized primarily to the dorsolateral regions. However, the pattern of brain activation induced by self-administered cocaine differed qualitatively. The area of major activation included anterior cingulate cortex, a region associated with the extended limbic system. When the effects of drug-associated stimuli were determined during extinction, there were marked increases in regional cerebral blood flow in the dorsomedial prefrontal cortex, indicating robust cortical activation. The results document that drug-associated stimuli can induce robust activation of prefrontal cortex in subjects with a complex history of drug use. We also have made significant progress in the development of BOLD fMRI protocols in conscious rhesus monkeys. The characteristic pattern of brain activation induced by cocaine was consistent with our previous studies using PET neuroimaging. Importantly, the effects of MDMA were qualitatively different and include the orbitofrontal cortex compared to the more medial extent in the anterior cingulate observed for cocaine. Collectively, these studies have identified neuronal targets to effectively reduce cocaine use and have characterized underling neurochemical mechanisms associated with therapeutic effects.